MicroRNAs (miRNAs) are global RNA regulators and important master controllers of the cell survival and proliferation pathways that are critically important in cancer development and tumor maintenance. Recent evidence from our group and others show that miRNA binding site polymorphisms in the 3' untranslated regions (3'UTRs) of mRNAs can strongly impact cancer risk, and that miRNA expression patterns in tumors are important biomarkers of outcome and treatment response. We hypothesize that advances in miRNA understanding can be applied to breast cancer. Breast cancer has 3 main sub-types based on expression of the receptor molecules ER (estrogen), PR (progesterone) and HER2/neu. Breast cancers negative for all of these receptors (triple negative breast cancer [TNBC]) have the worst outcome, and little is known about the etiology and risk factors for this sub-type. We hypothesize that advances in the novel area of miRNA biology can be applied to TNBC to identify novel biomarkers of risk and outcome as well as understand fundamental mechanisms of disease. The overall goal of this proposal is to study miRNA 3'UTR polymorphisms as initiating events in breast cancer, and to define the predictive role of miRNA expression patterns to identify biomarkers of response to therapy and outcome. We will ultimately test our findings that 3'UTR polymorphisms and misregulated miRNAs are key in breast cancer development using in vivo xenograft and transgenic mouse models. By accomplishing these aims we will be able to appropriately risk stratify women for the risk of developing breast cancer, as well as identify biomarkers predicting their response to therapy and ultimate outcome. We expect to gain insight into the fundamental biology behind breast cancer development, and to further identify miRNAs that are new targets in breast cancer response, to make significant strides towards personalized medicine for women. PUBLIC HEALTH RELEVANCE: Breast cancer is a common disease, with certain subtypes being very aggressive with poor outcome, such as triple negative breast cancer. While breast cancer for most women is likely due to multifactorial causes, there is a suspected inherited risk for some proportion of breast cancer cases, yet most of the genetic causes remain unknown. Through our understanding of breast cancer as well as microRNAs we have identified new biomarkers of breast cancer risk, which we believe will likely also be biomarkers of response to therapy, and will allow us to better prevent and treat breast cancer for women in the future.